1. Field of the Invention
The invention is an apparatus and method for determining the residual seal force of sealed containers. The invention particularly relates to the monitoring of production of parenteral pharmaceutical products, but can be applied to the determination of residual seal forces for many types of containers and for many types of products.
2. Description of the Related Art
Parenteral (injectable) pharmaceutical products are usually packaged in glass containers with a closure comprising a resilient sealing element held in place over the open end of the container by a cap. The cap usually is composed of aluminum, but may be composed of other materials. In the pharmaceutical packaging process, an apparatus applies a force to the resilient member, compressing the resilient member between a flange of the container and the cap. A skirt of the cap is crimped around the flange of the container. The cap thereby maintains a force on the resilient member, compressing the resilient member, sealing the container and protecting the pharmaceutical product against contamination.
The force exerted by the resilient member on the cap and container flange of a sealed container, and hence by the cap and container flange on the resilient member, is hereinafter referred to as the xe2x80x9cresidual seal forcexe2x80x9d (xe2x80x9cRSFxe2x80x9d). The compression of the resilient member in response to the residual seal force is hereinafter referred to as the xe2x80x9cresidual compression.xe2x80x9d Maintenance of an adequate residual seal force and hence a proper residual compression of the resilient member is important to maintaining a proper seal and to protecting the integrity of the pharmaceutical product enclosed within the container.
For purposes of this application, the term xe2x80x9cclosurexe2x80x9d is an assembly comprising the flange of the container, the resilient member covering the opening of the container and the cap compressing the resilient member and thereby sealing the container. A xe2x80x9cclosurexe2x80x9d may include a removable button allowing access to the resilient member so that a syringe may be inserted into the container, providing access to the parenteral pharmaceutical product.
Testing of the residual seal force of the closure is an important step in the package development and production of parenteral pharmaceutical products. The residual seal force of the closure may be tested in any of several ways. Selected containers may be tested by manually gripping the cap and attempting to rotate the cap. If the cap does not rotate, the closure is assumed to be adequately tight. The manual testing process is subjective, operator-dependent, imprecise and does not allow proactive process control.
Testing equipment exists, as described in U.S. Pat. Nos. 4,315,427 and 4,337,644 both issued to Leiter on Feb. 16, 1982 and Jul. 6, 1982 respectively. The Leiter patents reveal an apparatus and method whereby a slowly increasing force is applied to the closure while a human operator observes the skirt of the cap using a microscope. When the operator observes movement of the skirt, the operator assumes that the residual compression of the resilient member has been overcome and that the force exerted to overcome that residual compression equals the residual seal force. The Leiter apparatus and method is a manual method subject to operator control and operator error.
No existing method or apparatus provides for the automated testing of container closures for parenteral pharmaceutical products. No existing method or apparatus provides the algorithm of the present invention for determining residual seal force from stress-strain data collected by an automated testing apparatus.
The invention is an apparatus and method for determining the residual seal force for containers, particularly containers for parenteral pharmaceutical products. An automated press moves an anvil against the closure of a sealed container. The press automatically records distance as the anvil moves. At prescribed distances, the press automatically records the force applied to the anvil by the closure. The resulting data set comprises a sequence of data points for strain data (displacement of the closure) and stress data (force exerted by the closure in response to the strain). The data points can be plotted on a graph, approximating a stress-strain curve.
Stress-strain curves for the testing of parenteral container closures follow a predictable pattern. At the point at which the force exerted by the press overcomes the residual force exerted by the residual compression of the resilient member, the stress vs. strain graph shows a xe2x80x9ckneexe2x80x9d resulting from a reduction in slope. The stress at the knee of the stress-strain curve therefore defines the residual seal force.
The invention applies an algorithm to locate the knees of a series of data sets and hence to determine residual seal force. The strategy of the algorithm is to locate the knee using the technique of finding a minimum in the second derivative of the data set. In theory, location of a knee using a second derivative should be a straightforward exercise. In practice, the knee of the stress-strain curve is a subtle feature and difficult to isolate. The construction and configuration of containers coupled with limitations in the data collection create uncertainty and noise in the data and obscure the location of the knee. For example, the deformation of the button and cap are reflected in the stress-strain data, but do not represent the residual seal force. The algorithm of the present invention allows the knee, and hence the residual seal force, to be located despite the noise and uncertainty.
Since the data are discrete rather than a mathematical function, numerical analysis methods are used to determine a first derivative analogue and a second derivative analogue based on changes in slope over the span of two or more data points. Because the data are subject to minute variations due to the physics of the data collection and because derivatives tend to exacerbate these variations, data smoothing is used to reduce the variations. The first derivative analogue is determined and used to identify a strain range of interest. The strain range of interest comprises the region of the stress-strain curve falling between a lower bound defined by a local maximum of the first derivative analogue and an upper bound defined by a subsequent local minimum of the first derivative analogue. The minimum value of the second derivative analogue falling within the range of interest identifies a first possible location of the xe2x80x9ckneexe2x80x9d and hence a first candidate residual seal force.
The calculations are repeated using different data smoothing criteria. Several different data smoothing criteria are applied and a xe2x80x9ccandidate residual seal forcexe2x80x9d is calculated for each data-smoothing criterion. A xe2x80x9cconfidence levelxe2x80x9d is calculated for each candidate residual seal force. The confidence level represents an expression of the relative confidence that a particular candidate residual seal force is correct.
Four factors are used to calculate a confidence level. The first factor compares the value of the minimum of the second derivative analogue falling within the range of interest and the next-lowest minimum of the second derivative analogue occurring at any point in the data set. The greater the difference, the greater the confidence.
The second factor compares the value of the second derivative analogue minimum and the width of the second derivative analogue valley. The narrower and deeper the valley, the greater the confidence.
The third factor compares the first derivative analogue local maximum and the first derivative analogue valley used to define the range of interest. The greater the difference, the greater the confidence.
The fourth factor compares the value for residual seal force in question to the other values for residual seal force calculated using the same data points for other data smoothing criteria. The greater the agreement between the values, the greater the confidence.
The geometric mean of the four factors is calculated by multiplying the four factors and taking the fourth root of the resulting product. The geometric mean is adjusted to consider the variability in the data. The adjustment comprises drawing a hysteresis band on the graph of the second derivative analogue. The number of times that the graph of the second derivative analogue crosses through the hysteresis band is counted and the resulting number is subtracted from the geometric mean of the four factors. The result is the confidence level.
The candidate residual seal forces are ranked by confidence level. The calculated residual seal force corresponding to the data smoothing criterion producing the highest confidence level is selected as the residual seal force for the particular set of data points. The entire process is repeated twice, resulting in three sets of data points and three values for residual seal force.
If the three results agree adequately, the data is accepted and the three values are arithmetically averaged to determine the final residual seal force. If the three results do not agree, the result is rejected and additional data collected.
In the method of the invention, data collection is automated, as are data manipulation and calculation. The value for residual seal force determined for a container may be used to control a process, such as a packaging process for pharmaceutical or other products. The determined value of residual seal force for a container also may be used to design or select appropriate packaging for a product, such as a pharmaceutical product.